Youth with family history (FH+) of substance use disorders (SUDs) are at increased risk for developing SUDs. Similarly, childhood attention deficit hyperactivity disorder (ADHD) is considered to be a risk factor for developing SUDs. Recent research has suggested a close association between SUDs and impaired inhibitory control. As such, it is crucial to examine common and distinct neural alterations associated with inhibitory control in these at-risk groups, particularly prior to the initiation of heavy substance use. This paper reviews the functional magnetic resonance imaging (fMRI) literature of inhibitory control in these two at-risk youth populations (FH+ and ADHD), specifically considering studies that used motor response inhibition tasks (Go/No-Go or Stop Signal). Across the selected fMRI studies, we discovered no common alteration in the at-risk groups, but found neural alterations specific to each at-risk group. In FH+ youth and youth who transitioned into heavy substance use, blunted activation in the lateral part of the frontal pole (FP-lat) was most reliably observed. Importantly, longitudinal studies indicate that the blunted FP-lat activation may predict later SUDs, irrespective of the presence of FH+. In regards to ADHD, blunted activation was observed in the right dorsal anterior cingulate cortex (dACC) and left caudate. Of note, similar blunted dACC activation was also reported by one FH+ study, and thus, we cannot preclude a possibility that the right dACC activity may be a potential common alteration in both at-risk groups, particularly given a limited number of FH+ studies in the current review. Research challenges remain, and large-scale, longitudinal efforts will help determine the neurobiological markers predictive of SUDs among at-risk adolescents, including those with FH+, as well as those with ADHD and other psychiatric disorders.